147494-90-4Relevant academic research and scientific papers
SAR evolution towards potent C-terminal carboxamide peptide inhibitors of Zika virus NS2B-NS3 protease
Abate, Luigi,Amaudrut, Jerome,Beghetto, Elisa,Bianchi, Elisabetta,Bresciani, Alberto,Colarusso, Stefania,Conte, Immacolata,Ferrigno, Federica,Missineo, Antonino,Montalbetti, Christian,Ontoria, Jesus M.,Paonessa, Giacomo,Pavone, Francesca,Ponzi, Simona,Tomei, Licia,Toniatti, Carlo
, (2022/02/05)
Zika virus (ZIKV) is a member of the Flaviviridae family that can cause neurological disorders and congenital malformations. The NS2B-NS3 viral serine protease is an attractive target for the development of new antiviral agents against ZIKV. We report here a SAR study on a series of substrate-like linear tripeptides that inhibit in a non-covalent manner the NS2B-NS3 protease. Optimization of the residues at positions P1, P2, P3 and of the N-terminal and C-terminal portions of the tripeptide allowed the identification of inhibitors with sub-micromolar potency with phenylglycine as arginine-mimicking group and benzylamide as C-terminal fragment. Further SAR exploration and application of these structural changes to a series of peptides having a 4-substituted phenylglycine residue at the P1 position led to potent compounds showing double digit nanomolar inhibition of the Zika protease (IC50 = 30 nM) with high selectivity against trypsin-like proteases and the proteases of other flavivirus, such as Dengue 2 virus (DEN2V) and West Nile virus (WNV).
